The present invention relates to a process for producing O-alkylrapamycin derivatives by reaction between rapamycin and alkyl triflate.
Rapamycin is one of macrolide antibiotics produced by Streptomyces hygroscopicus. It exhibits immunosuppresive actions, carcinostatic actions, and antifungal actions. Because of such useful pharmaceutical activity, much has been reported about rapamycin derivatives (See Drugs of Future, 1999, 24(1): 22–29).
On the other hand, synthesis of rapamycin derivatives has been reported by Cottens et al (See WO94/09010 official gazette). This document discloses a process for producing an O-alkylrapamycin derivative by reaction between rapamycin and alkyl triflate in the presence of lutidine in toluene (as a solvent). However, it mentions nothing about the yield that is attained by the disclosed process. Further investigation by the present inventors revealed that the yield is only 23% (refer to Comparative Example 1 mentioned later), which suggests that the O-alkylating reaction does not proceed smoothly as desired. Therefore, a great improvement in the process of synthesis has been required for effective use of very expensive rapamycin.